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Rifampicin

Inhibitor of Nucleic Acid Synthesis
Rifampicin
Rifampicin structure
CAS No.
13292-46-1
Chemical Name:
Rifampicin
Synonyms
RIF;ARHF;RHOF;rifa;FaMcin;l-5103;Eremfat;Dipicin;Abrifam;Rifater
CBNumber:
CB7474473
Molecular Formula:
C43H58N4O12
Formula Weight:
822.94
MOL File:
13292-46-1.mol

Rifampicin Properties

Melting point:
183°C (dec.)
Boiling point:
761.02°C (rough estimate)
Density 
1.1782 (rough estimate)
refractive index 
1.6000 (estimate)
storage temp. 
2-8°C
solubility 
chloroform: soluble50mg/mL, clear
pka
1.7, 7.9(at 25℃)
form 
crystalline
color 
faint red to very dark red
Water Solubility 
Soluble in DMSO or methanolSoluble in water, ethyl acetate, chloroform, methanol, tetrahydrofuran and dimethyl sulfoxide.
Merck 
14,8216
BRN 
5723476
FDA UNII
VJT6J7R4TR
NCI Dictionary of Cancer Terms
rifampin
ATC code
J04AB02
Proposition 65 List
Rifampin
IARC
3 (Vol. 24, Sup 7) 1987
EPA Substance Registry System
Rifampin (13292-46-1)
SAFETY
  • Risk and Safety Statements
Symbol(GHS) 
GHS07
Signal word  Warning
Hazard statements  H227-H302-H315-H319-H335
Precautionary statements  P301+P312+P330-P305+P351+P338-P261-P280a-P304+P340-P405-P501a-P264-P270-P280-P302+P352+P332+P313+P362+P364-P305+P351+P338+P337+P313-P501-P210e-P370+P378a-P403+P235
Hazard Codes  Xn,Xi
Risk Statements  22-36/37/38-36/38
Safety Statements  26-36-37/39
WGK Germany  3
RTECS  VJ7000000
8-10-21
HS Code  29419000
Toxicity LD50 in mice, rats (mg/kg): 885, 1720 orally; 260, 330 i.v.; 640, 550 i.p. (Fürész)

Rifampicin price More Price(33)

Manufacturer Product number Product description CAS number Packaging Price Updated Buy
Sigma-Aldrich 46713 Rifampicin VETRANAL 13292-46-1 100mg $40.2 2018-11-20 Buy
Sigma-Aldrich 557303 Rifampicin - CAS 13292-46-1 - Calbiochem Antibiotic that specifically inhibits DNA-dependent RNA polymerase in bacteria by forming an inactive complex. 13292-46-1 1 g $85.65 2021-03-22 Buy
Sigma-Aldrich R0700000 Rifampicin European Pharmacopoeia (EP) Reference Standard 13292-46-1 $190 2021-03-22 Buy
Sigma-Aldrich AXYMCT060CS Microtubes size 0.6?mL, clear, pkg of 10x500tubes/cs, sterile 13292-46-1 1 pkg $207 2021-03-22 Buy
Sigma-Aldrich Z763098 Prism™ Mini Centrifuge AC/DC input 120 V AC 13292-46-1 1 ea $219 2021-03-22 Buy

Rifampicin Chemical Properties,Uses,Production

Inhibitor of Nucleic Acid Synthesis

Rifampicin and other compounds of the ansamycin group specifically inhibit DNA-dependent RNA polymerase; that is, they prevent the transcription of RNA species from the DNA template. Rifampicin is an extremely efficient inhibitor of the bacterial enzyme, but fortunately eukaryotic RNA polymerase is not affected. RNA polymerase consists of a core enzyme made up of four polypeptide subunits, and rifampicin specifically binds to the β subunit where it blocks initiation of RNA synthesis, but is without effect on RNA polymerase elongation complexes. The structural mechanism for inhibition of bacterial RNA polymerase by rifampicin has recently been elucidated. The antibiotic binds to the β subunit in a pocket which directly blocks the path of the elongating RNA chain when it is two to three nucleotides in length. During initiation the transcription complex is particularly unstable and the binding of rifampicin promotes dissociation of short unstable RNA DNA hybrids from the enzyme complex. The binding pocket for rifampicin, which is absent in mammalian RNA polymerases, is some 12 Å away from the active site.

Description

Rifampicin is a semisynthetic derivative of rifamicin B, a macrolactam antibiotic and one of more than five antibiotics from a mixture of rifamicins A, B, C, D, and E, which is called a rifamicin complex, which is produced by actinomycetes Streptomyces mediteranei (Nocardia mediteranei). It was introduced into medical practice in 1968. Synthesis of rifampicin begins with an aqueous solution of rifamicin, which under the reaction conditions is oxidized to a new derivative of rifamicin S (32.7.4), with the intermediate formation of rifamicin O (32.7.3). Reducing the quinone structure of this product with hydrogen using a palladium on carbon catalyst gives rifamicin SV (32.7.5). The resulting product undergoes aminomethylation by a mixture of formaldehyde and pyrrolidine, giving 3-pyrrolidinomethylrifamicin SV (32.7.6). Oxidizing the resulting product with lead tetracetate to an enamine and subsequent hydrolysis with an aqueous solution of ascorbic acid gives 3-formylrifamicin SV (32.7.7). Reacting this with 1-amino-4-methylpiperazine gives the desired rifampicin (32.7.8).
CB7474473.jpg

Chemical Properties

Red to Orange Crystalline Solid

Uses

Semisynthetic antibiotic. Antibacerial (tuberculostatic)

Uses

antibacterial (tuberculostatic)

Uses

Rifampin is used as an antibiotic. It is a semisynthetic derivative of rifamycin B, a macrocyclic antibiotic produced by the mold Streptomyces mediterranei. Rifampin is used for the treatment of tuberculosis, brucellosis, Staphlococcus aureus, and other infectious diseases.

Indications

Rifampin (300 to 450 mg daily) is very effective in relieving the pruritus of primary biliary cirrhosis, by inhibiting hepatic bile uptake and stimulating mixed-function oxidases. Liver enzymes should be monitored to detect druginduced hepatitis.

Definition

ChEBI: A member of the class of rifamycins that is a a semisynthetic antibiotic derived from Amycolatopsis rifamycinica (previously known as Amycolatopsis mediterranei and Streptomyces mediterranei)

brand name

Rifadin (Sanofi Aventis); Rimactane (Actavis).

Antimicrobial activity

It exhibits potent activity in vitro against Gram-positive cocci, including methicillin-resistant staphylococci (MIC <0.025–0.5 mg/L) and penicillinresistant pneumococci. Enterococci are less susceptible. Gram-positive bacilli, including Bacillus spp., Clostridium difficile, Corynebacterium spp. and Listeria monocytogenes, are highly susceptible (MIC 0.025–0.5 mg/L). The pathogenic Neisseria and Moraxella spp. are also highly susceptible.
Enteric Gram-negative bacteria are generally less sensitive (MIC 1–32 mg/L), but Bacteroides fragilis is highly susceptible. Among other Gram-negative bacilli, Haemophilus influenzae, H. ducreyi, Flavobacterium meningosepticum and Legionella spp. are highly susceptible (MIC <0.025–2 mg/L). Chlamydia trachomatis and Chlamydophila psittaci are inhibited by low concentrations (0.025–0.5 mg/L).
Most strains of M. tuberculosis, M. kansasii and M. marinum are inhibited by <0.01–0.1 mg/L, but M. fortuitum and members of the M. avium complex are resistant. M. leprae is highly sensitive.
Rifampicin is active against some eukaryotic parasites through inhibition of the prokaryote-like polymerase of kinetoplasts or mitochondria. Maturation of Plasmodium falciparum is inhibited by 2–10 mg/L; at higher concentrations Leishmania spp. are also inhibited.
High concentrations inhibit growth of a variety of poxviruses by interference with viral particle maturation; viral reverse transcriptase is unaffected.

Acquired resistance

Most large bacterial populations contain resistant mutants, which readily emerge in the presence of the drug and can emerge during treatment. The mutation rate to resistance in Staph. aureus, Str. pyogenes, Str. pneumoniae, Esch. coli and Proteus mirabilis is about 10–7 and that to M. tuberculosis and M. marinum 10–9–10–10. Primary resistance in M. tuberculosis remained low for many years, but is increasing.
Resistance is of the one-step type, and several classes of mutants exhibiting different degrees of resistance can be selected by exposing a large population to a relatively low concentration of the drug. Some of these mutants may be susceptible to other rifamycin derivatives.
Resistance is due to a change in a single amino acid of the β subunit of DNA-dependent RNA polymerase, which no longer forms a stable complex with rifampicin. It is not transferable and there is no cross-resistance with any other antibiotic class. The susceptible strains of the gastrointestinal flora become rapidly resistant during rifampicin treatment without alteration in the flora composition, and revert to susceptibility within a few weeks of cessation of treatment.

Pharmaceutical Applications

Rifampin (USAN). Molecular weight: 822.95.
A semisynthetic derivative of rifamycin SV, available for oral administration or intravenous infusion and in several combined formulations with other antimycobacterial drugs. It is poorly soluble in water, but soluble in organic solvents.

Mechanism of action

Rifampin is a semisynthetic macrocyclic antibiotic produced from Streptomyces mediterranei. It is a large lipidsoluble molecule that is bactericidal for both intracellular and extracellular microorganisms. Rifampin binds strongly to the β-subunit of bacterial DNA-dependent RNA polymerase and thereby inhibits RNA synthesis. Rifampin does not affect mammalian polymerases.

Pharmacology

Rifampin is well absorbed orally, and a peak serum concentration is usually seen within 2 to 4 hours. Drug absorption is impaired if rifampin is given concurrently with aminosalicylic acid or is taken immediately after a meal. It is widely distributed throughout the body, and therapeutic levels are achieved in all body fluids, including cerebrospinal fluid. Rifampin is capable of inducing its own metabolism, so its half-life can be reduced to 2 hours within a week of continued therapy. The deacetylated form of rifampin is active and undergoes biliary excretion and enterohepatic recirculation. Most of the drug is excreted into the GI tract and a small amount in the urine.Moderate dose adjustment is required in patients with underlying liver disease.

Pharmacokinetics

Oral absorption:>90%
Cmax300 mg oral :4 mg/L after 2 h
600 mg oral:10 mg/L after 2 h
Plasma half-life:2.5 h
Volume of distribution:1.5 L/kg
Plasma protein binding:80%
absorption
Rifampicin is virtually completely absorbed when administered orally, but substantial differences in blood levels have been reported in comparisons of capsules or tablets from different manufacturers. Peak plasma levels differ noticeably between individuals. Food affects absorption, the peak plasma levels being delayed and about 2 mg/L lower after a meal. Although the AUC and the length of time for which effective antibacterial levels are maintained are little affected, it is preferable that patients take the drug before meals.
Intravenous administration produces AUCs and elimination half-lives similar to those obtained after oral doses.
Distribution
The lipid solubility of the drug facilitates its distribution. It is widely distributed in the internal organs, bones and fluids, including tears, saliva, ascitic fluid and abscesses. It penetrates into cells and is active against intracellular bacteria. Low concentrations are found in the cerebrospinal fluid (CSF), but these are substantially higher when the meninges are inflamed. Concentrations around 60% of the simultaneous plasma value were found in the heart valves of patients receiving a 600 mg dose before surgery.
Metabolism
Rifampicin is metabolized principally to its desacetyl derivative, which is also antimicrobially active, and this process is accelerated by its stimulatory effect on hepatic microsomal enzymes. As a consequence, hepatic clearance increases on continuous administration and, especially with high doses, the serum half-life becomes shorter after a few days of treatment.
excretion
The main route of elimination is secretion into the bile, a process that is dose dependent, being efficient at low dosage but limited at high dosage. As a result, the dose determines the proportion excreted via the bile or passing the liver to be excreted in the urine. Because there is a limit to the rate at which the liver can deliver the drug to the bile, the elimination half-life after a 600 mg dose rises to 3 h and may be as long as 5 h with a 900 mg dose.
The desacetyl compound is mainly found in the bile, where the parent compound accounts for only 15% of the total. Plasma levels are increased by hepatic insufficiency and biliary obstruction, and by probenecid, which depresses hepatic uptake. The drug escaping biliary excretion appears in the urine, to which it imparts an orange–red color, the parent compound and the desacetyl metabolites being present in about equal proportions. The plasma concentration and half-life are not significantly affected by renal failure. The drug is not removed by hemodialysis.

Clinical Use

The incidence of hepatotoxicity was significantly higher when rifampin was combined with isoniazid than when either agent was combined with ethambutol. Allergic and sensitivity reactions to rifampin have been reported, but they are infrequent and usually not serious. Rifampin is a powerful inducer of hepatic cytochrome P450 oxygenases. It can markedly potentiate the actions of drugs that are inactivated by these enzymes. Examples include oral anticoagulants, barbiturates, benzodiazepines, oral hypoglycemic agents, phenytoin, and theophylline. Rifampin is also used to eradicate the carrier state in asymptomatic carriers of Neisseria meningitidis to prevent outbreaks of meningitis in high-risk areas such as military facilities. Serotyping and sensitivity tests should be performed before its use because resistance develops rapidly. However, a daily dose of 600 mg of rifampin for 4 days suffices to eradicate sensitive strains of N. meningitidis. Rifampin has also been very effective against M. leprae in experimental animals and in humans. When it is used in the treatment of leprosy, rifampin should be combined with dapsone or some other leprostatic agent to minimize the emergence of resistant strains of M. leprae. Other, nonlabeled uses of rifampin include the treatment of serious infections such as endocarditis and osteomyelitis caused by methicillin-resistant S. aureus or S. epidermidis, Legionnaires disease when resistant to erythromycin, and prophylaxis of H. influenzae induced meningitis. Rifampin occurs as an orange to reddish brown crystalline powder that is soluble in alcohol but only sparingly soluble in water. It is unstable to moisture, and a desiccant (silica gel) should be included with rifampin capsule containers. The expiration date for capsules stored in this way is 2 years.

Clinical Use

Tuberculosis (in combination with other antituberculosis agents; see Ch. 58)
Leprosy (in combination with other antileprotic agents; see Ch. 57)
Serious infection with multiresistant staphylococci and pneumococci (in combination with a glycopeptide)
Elimination of nasopharyngeal carriage of Neisseria meningitidis and H. influenzae.

Clinical Use

Rifampin is a first-line antitubercular drug used in the treatment of all forms of pulmonary and extrapulmonary tuberculosis. Rifampin is an alternative to isoniazid in the treatment of latent tuberculosis infection. Rifampin also may be combined with an antileprosy agent for the treatment of leprosy and to protect those in close contact with patients having H. influenza type b and N. meningitidis infection; rifampin is also used in methicillin-resistant staphylococcal infections, such as osteomyelitis and prosthetic valve endocarditis.

Side effects

The most commonly observed side effects are GI disturbances and nervous system symptoms, such as nausea, vomiting, headache, dizziness, and fatigue.Hepatitis is a major adverse effect, and the risk is highest in patients with underlying liver diseases and in slow isoniazid acetylators; the rate of hepatotoxicity is increased if isoniazid and rifampin are combined.
Other major untoward reactions are the result of rifampin’s ability to induce hepatic cytochrome P-450 enzymes, leading to an increased metabolism of many drugs; this action has especially complicated the treatment of tuberculosis in HIV-infected patients whose regimen includes protease inhibitors and nonnucleoside reverse transcriptase. Since rifabutin has relatively little of these effects, it is commonly substituted for rifampin in the treatment of tuberculosis in HIV-infected patients.
Hypersensitivity reactions, such as pruritus, cutaneous vasculitis, and thrombocytopenia, are seen in some patients, and an immune-mediated systemic flulike syndrome with thrombocytopenia also has been described. Rifampin imparts a harmless red-orange color to urine, feces, saliva, sweat, tears, and contact lenses. Patients should be advised of such discoloration of body fluids.

Side effects

Rifampicin is relatively non-toxic, even when administered for a long period (as in the treatment of tuberculosis). However, several unwanted effects, including pink staining of soft contact lenses, are associated with its use. Other reactions can be divided into those associated with daily or intermittent administration, and those found only with intermittent therapy.

Safety Profile

Suspected carcinogen with experimental neoplastigenic and teratogenic data. Poison by intraperitoneal and intravenous routes. Moderately toxic to humans by ingestion. Moderately experimentally toxic by ingestion and subcutaneous routes. Human systemic effects by ingestion: conjunctiva irritation, iritis (inflammation of the iris), other eye effects, dermatitis. Experimental reproductive effects. Human mutation data reported. When heated to decomposition it emits toxic fumes of NOx.

Environmental Fate

Physicochemical Properties
Rifampicin or rifampin is a red to orange odorless powder. It is very slightly soluble in water (1 g per 762 ml at pH <6), acetone, carbon tetrachloride, ethanol, and ether; freely soluble in chloroform and dimethyl sulfoxide (DMSO); soluble in ethyl acetate and methanol and tetrahydrofuran. The solubility of rifampin increases at acidic pH. Rifampin has a melting point of 138–188 °C and a pKa of 1.7 related to the 4-OH moiety and 7.9 related to the 3-piperazine nitrogen moiety. In 1% suspension in water, the pH is 4.5–6.5.
Exposure Pathway
Ingestion is the most common route of exposure. Rifampin is available in oral and parenteral forms.
Toxicokinetics
Rifampin is rapidly and nearly completely absorbed from the gastrointestinal tract. Peak serum levels are seen within 2–4 h. Food, antacids, ketoconazole, and aminosalicylic acid interfere with absorption and delay peak levels. If these agents are used concurrently, they should be administered separately at an interval of at least 8 h. Massive ingestions in the overdose setting may also delay absorption. Protein binding is 75–90%. The volume of distribution is approximately 1 l kg-1. Rifampin undergoes hepatic deacetylation to an active metabolite. Both rifampin and its deacetylated metabolite are excreted into the bile. Rifampin and to a lesser extent its deacetylated metabolite undergo enterohepatic recirculation. The half-life of therapeutic doses of rifampin is 1.5–5 h. The half-life is shortened after regular use due to induction of hepatic enzymes. Chronic liver disease increases the half-life. The kinetics are not well described in the overdose setting.

Purification Methods

This macrolide antibiotic crystallises form Me2CO in red-orange plates. It has UV max at 237, 255, 334, and 475nm ( 33,200, 32,100, 27,000 and 15,400) at pH 7.38. It is stable in Me2SO and H2O and is freely soluble in most organic solvents but slightly soluble in H2O at pH <6. [Binda et al. Arzneim.-Forsch 21 1907 1971.] It inhibits cellular RNA synthesis without affecting DNA [Calvori et al. Nature 207 417 1965].

Toxicity evaluation

In the acute overdose setting, the mechanism of toxicity is not defined. A number of toxic reactions occurring with intermittent dosing schedules or on reexposure are postulated to be due to the presence of antirifampin antibodies.

Rifampicin Preparation Products And Raw materials

Raw materials

Preparation Products


Rifampicin Suppliers

Global( 497)Suppliers
Supplier Tel Fax Email Country ProdList Advantage
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View Lastest Price from Rifampicin manufacturers

Image Release date Product Price Min. Order Purity Supply Ability Manufacturer
2021-12-08 Rifampicin
13292-46-1
US $0.00 / KG 100g 98%+ 100kg WUHAN CIRCLE POWDER TECHNOLOGY CO.,LTD
2021-12-01 Rifampicin
13292-46-1
US $10.00 / KG 1KG 99% 10 ton Hebei Crovell Biotech Co Ltd
2021-11-16 Rifampicin
13292-46-1
US $0.00 / KG 1g 99% 50kg WUHAN CIRCLE POWDER TECHNOLOGY CO.,LTD

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